EP1075284B1 - Verwendung von einem farbstoff zum erleichtern der augennetzhautoperationen - Google Patents

Verwendung von einem farbstoff zum erleichtern der augennetzhautoperationen Download PDF

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Publication number
EP1075284B1
EP1075284B1 EP99921290A EP99921290A EP1075284B1 EP 1075284 B1 EP1075284 B1 EP 1075284B1 EP 99921290 A EP99921290 A EP 99921290A EP 99921290 A EP99921290 A EP 99921290A EP 1075284 B1 EP1075284 B1 EP 1075284B1
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EP
European Patent Office
Prior art keywords
retinal
dye
membrane
use according
membranes
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Revoked
Application number
EP99921290A
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English (en)
French (fr)
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EP1075284A1 (de
Inventor
Gerrit Reinold Jacob Melles
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Individual
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Individual
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Priority claimed from EP98201542A external-priority patent/EP0963759A1/de
Application filed by Individual filed Critical Individual
Priority to EP99921290A priority Critical patent/EP1075284B1/de
Priority to SI9930261T priority patent/SI1075284T1/xx
Publication of EP1075284A1 publication Critical patent/EP1075284A1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • the invention relates to the field of ocular surgery, in particular to surgical procedures for vitreo-retinal surgery.
  • the retina In the normal eye, the retina is located in the posterior segment of the eye, behind the corpus vitreum.
  • the retina is a thin, translucent membrane resting on a single layer of pigmented epithelium, extending from the ora serrata to the optic disc. It consists of photoreceptor cells (rods and cones), which are connected to neuron pathways terminating in nonmyelinated fibers. These are combined to form the optic nerve.
  • the innermost structure of the retina is the membrana limitans interna.
  • the vitreous is a clear, transparent, semi-solid gel which occupies about two thirds of the volume of the globe extending from the lens to the optic disc. It is a connective tissue space with the greater portion of the space made up of intercellular collagen and hyaluronic acid networks.
  • the vitreous base represents the most solid attachment of the vitreous to the wall of the eye. It straddles the ora extending anteriorly on the pars plana over 1.5 to 2 mm and posteriorly on the retina over 3 to 4 mm.
  • the posterior vitreous separates from the retina and collapses anteriorly toward the vitreous base.
  • Most retinal tears are caused by spontaneous or traumatic PVD, since traction on the vitreous here causes tenting of the retina and ciliary body. Retinal detachment may occur (sub)acutely.
  • PVR proliferative vitreoretinopathy
  • Retinal membrane peeling and dissection is performed to relieve the traction on the retinal surface, so that the contracted tissue can be flattened out again. Removal of the membranes is often difficult, because the membranes consist of fibrous tissue having nearly the same color as the underlying retina. Improper visualization of the membranes on the retina therefore bears the risk of incomplete removal of the fibrous tissue, so that insufficient relaxation of the retina is achieved, or damage to the underlying retina, compromising its local function.
  • the present invention seeks to overcome the problems associated with poor visibility of the retinal membranes during vitreo-retinal surgery. It is an object of the invention to make it possible to visually distinguish the retinal membranes from the underlying retina, so that the membranes can be better identified during surgery, for example to prevent the uncomplete removal of the membranes, or damage to the retina itself.
  • the invention relates to the use of at least one vital dye for the manufacture of a composition for staining a retinal membrane in an eye, preferably in a method for performing retinal membrane removal.
  • the outer surface of the retinal membranes is selectively stained, by which is meant that the retinal tissue beneath the membranes is substantially not, or at least to a significantly lesser extent than the retinal membranes, stained. Accordingly, during the removal of the membranes, a clear distinction can be observed between the membranes that are being removed, and the underlying retina. This distinction facilitates the controlled removal of the membranes, and reduces the risk of inadvertent damage to the retina.
  • the retinal membranes are stained using a vital dye.
  • a vital dye is a dye which has a sufficient coloring, or staining capacity at a concentration which is physiologically and toxicologically acceptable.
  • the minimum amount of dye which is necessary to provide sufficient staining for a useful coloring to be visible should so be low that no, or hardly any, adverse toxic effects occur.
  • the dye is not or hardly toxic for the retina and adjacent structures. It is further preferred, that substantially no traces of the dye are present in the eye, shortly after the vitreo-retinal procedure has been completed. As a result, there is hardly any risk of the patient experiencing any side-effects from the use of the dye.
  • Suitable vital dyes include azafloxin, basic blue (nil blue sulphate), bismarck brown, basic red (rhodamine 6G), bengal red, brilliant crysyl blue, eosin, fluorescein, gentian violet, indocyanine green, janus green, methylene green, methylene blue, neutral red, trypan blue, and trypan red.
  • Particularly suitable examples of vital dyes which are capable of staining tissue or a tissue component, substantially without diffusing through said tissue are dyes having the formula (I) wherein R 1 and R 2 are the same or different arylgroups, and wherein R 3 and R 4 are independently chosen from hydrogen, methyl, ethyl, methoxy, amino, hydroxyl, and sulfonate.
  • R 1 and R 2 are preferably the same and formed by substituted naphtylgroups.
  • the naphtylgroups are substituted with one or more of sulfonate groups, amino groups and hydroxyl groups.
  • the dye is chosen from the group of trypan blue, trypan red, brilliant crysyl blue, and indocyanine green. It has been found that these dyes provide a clearly visible staining at very low amounts. Also, they have an extremely advantageous toxicity profile. More preferably, the dye is trypan blue.
  • the dye is preferably used as a physiologically compatible solution.
  • the dye is formulated in an aqueous salt solution, which is isotone with ocular fluid.
  • the salt is preferably sodium chloride, sodium phosphate, potassium chloride, calcium chloride, magnesium chloride, or a combination thereof. Suitable examples are Balanced salt solution or Hartmann's lactated Ringer's solution (Nuijts RMMA, Edelhauser HF, Holley GP, "Intraocular irrigating solutions: a comparison of Hartmann's lactated Ringer's solution, BSS and BSS plus", Clin. Exp. Ophtamol., vol. 233 (1995), pp. 655-661).
  • the salt concentration will be in the range of 0.8 to 1.0 wt.%, based on the weight of the solution.
  • the solution has a neutral pH, i.e. a pH between 6.5 and 7.5.
  • a suitable buffer which has the properties to be of use in opthtalmic applications.
  • An example of a suitable buffer is phosphate buffered NaCl, commercially available at NPBI, Emmer-Compascuum, The Netherlands.
  • the dye solution may be desired to formulate said solution as a dispersion, or a viscous or viscoelastomeric solution, for example using hyaluronic acid (see WO-A-96/32929).
  • a higher viscosity may be desired in order to achieve better adherence of the dye to the retinal membranes. It will be well within the standard expertise of the skilled person to select a suitable form for the solution.
  • the concentration of the dye or the mixture of dyes in the solution will preferably be between 0.01 and 3 wt.%, more preferably between 0.05 and 0.5 wt.%, based on the weight of the solution. Within this range, the concentration may be adapted to the toxicity and coloring characteristics of the dye used. It is preferred that such an amount is chosen that an optimal staining effect is achieved, while at the same time the risk of possible damage to the eye or any part thereof due to the toxicity of the dye is minimized.
  • a method comprising staining of a retinal membrane using a composition as described above is preferably employed as part of a vitreo-retinal surgical procedure.
  • a surgical procedure may for instance be based on one of the following techniques: retinal detachment surgery, macula Pucker removal, or macular hole surgery.
  • the surgical procedure is performed on a mammalian eye, more preferably on a human eye.
  • the vitreous (ocular gel) is removed and the posterior segment of the eye is filled with air.
  • a few drops of the above described solution comprising the dye in an appropriate concentration is applied onto the retinal membranes.
  • the application of the solution may be carried out by bringing a canula that is attached to a syringe containing the dye onto the vitreous cavity, and to inject a few drops of the dye, generally less than 1 ml, onto the retinal membranes.
  • the vitreous cavity is filled with air, so that the concentration of the dye in the solution is not lowered by liquid vitreous, and the dye can be applied onto a specific retinal area.
  • the dye can be administered in a higher concentration into the liquefied vitreous, or a dispersion of the dye in a viscous or viscoelastomeric solution can be used.
  • excess of dye is washed out by irrigating the vitreous cavity, leaving a faint but clear staining of the retinal membranes, after which the surgery can be continued using routine techniques.
  • the irrigation may be carried out by using Balanced salt solution or any other solution that is commonly used in intraocular surgical procedures.
  • the membranes can be removed using routine surgical techniques. Although care should be taken that as much of the retinal membranes as possible is removed, it will be clear that it is possible that small parts of the retinal membranes are unintentionally not removed and remain present after the surgery.
  • the retinal membranes can be identified because of the difference in color between the stained retinal membranes and the non-staining underlying retina, so that the outline of a retinal membrane can be visualized during its removal.
  • the retinal membrane(s) was then removed using routine surgical techniques, for example 'membrane peeling' or 'epiretinal membrane removal'.
  • the removal of the membranes was controlled by visualization of the blue stained membrane(s), whereas the surrounding or underlying retina was seen as gray tissue adjacent to the membrane or in the area where the membrane(s) had been removed.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Optics & Photonics (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Materials For Medical Uses (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Prostheses (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compositions Of Oxide Ceramics (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Orthopedics, Nursing, And Contraception (AREA)
  • Medicinal Preparation (AREA)

Claims (11)

  1. Verwendung von mindestens einem Lebendfarbstoff für die Herstellung einer Zusammensetzung zum Färben einer Retinamembran in einem Auge.
  2. Verwendung gemäß Anspruch 1, worin die Retinamembran in einem Verfahren zum Durchführen der Entfernung der Retinamembran gefärbt wird.
  3. Verwendung gemäß Anspruch 1 oder 2, worin die Retinamembran eine proliferierende Vitreo-Retinamembran ist.
  4. Verwendung gemäß Anspruch 1 oder 2, worin die Retinamembran eine Epiretinamembran ist.
  5. Verwendung gemäß irgendeinem der vorangegangenen Ansprüche, worin die Retinamembran durch Auftragen des Farbstoffes auf die Membran gefärbt wird.
  6. Verwendung gemäß irgendeinem der Ansprüche 2-5, worin das Verfahren Teil eines Vitreo-Retinaoperationsverfahrens ist.
  7. Verwendung gemäß irgendeinem der vorangegangenen Ansprüche, worin der Farbstoff in der Lage ist, Gewebe zu färben, ohne durch das Gewebe zu diffundieren.
  8. Verwendung gemäß Anspruch 7, worin der Farbstoff aus der Gruppe Trypanblau (trypan blue), Trypanrot (trypan red), Brilliantcrysylblau (brilliant crysyl blue) und Indocyaningrün (indocyanine green) gewählt wird.
  9. Verwendung gemäß irgendeinem der vorangegangenen Ansprüche, worin die Zusammensetzung die Form einer physiologisch verträglichen Lösung hat.
  10. Verwendung gemäß Anspruch 9, worin der Farbstoff in einer Konzentration zwischen 0,01 und 3 Gew.-%, basierend auf dem Gewicht der Lösung, vorliegt.
  11. Verwendung gemäß Anspruch 9 oder 10, worin die Lösung ferner ein Salz zwischen 0,8 und 1,0 Gew.-%, basierend auf dem Gewicht der Lösung, beinhaltet.
EP99921290A 1998-05-08 1999-05-07 Verwendung von einem farbstoff zum erleichtern der augennetzhautoperationen Revoked EP1075284B1 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99921290A EP1075284B1 (de) 1998-05-08 1999-05-07 Verwendung von einem farbstoff zum erleichtern der augennetzhautoperationen
SI9930261T SI1075284T1 (en) 1998-05-08 1999-05-07 The use of a vital dye for facilitating surgical procedures for vitreo-retinal surgery

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP98201542 1998-05-08
EP98201542A EP0963759A1 (de) 1998-05-08 1998-05-08 Verwendung von einem Farbstoff zum Erleichtern der Entfernung einer Augenlinsentrübung
EP98202751A EP0974367A1 (de) 1998-05-08 1998-08-17 Verwendung von einem Farbstoff zum Erleichtern der Augennetzhautoperationen
EP98202751 1998-08-17
EP99921290A EP1075284B1 (de) 1998-05-08 1999-05-07 Verwendung von einem farbstoff zum erleichtern der augennetzhautoperationen
PCT/NL1999/000283 WO1999058159A1 (en) 1998-05-08 1999-05-07 The use of a vital dye for facilitating surgical procedures for vitreo-retinal surgery

Publications (2)

Publication Number Publication Date
EP1075284A1 EP1075284A1 (de) 2001-02-14
EP1075284B1 true EP1075284B1 (de) 2003-02-12

Family

ID=26150325

Family Applications (2)

Application Number Title Priority Date Filing Date
EP98202751A Withdrawn EP0974367A1 (de) 1998-05-08 1998-08-17 Verwendung von einem Farbstoff zum Erleichtern der Augennetzhautoperationen
EP99921290A Revoked EP1075284B1 (de) 1998-05-08 1999-05-07 Verwendung von einem farbstoff zum erleichtern der augennetzhautoperationen

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP98202751A Withdrawn EP0974367A1 (de) 1998-05-08 1998-08-17 Verwendung von einem Farbstoff zum Erleichtern der Augennetzhautoperationen

Country Status (16)

Country Link
US (1) US6696430B1 (de)
EP (2) EP0974367A1 (de)
JP (1) JP3469198B2 (de)
KR (1) KR100711269B1 (de)
AT (1) ATE232400T1 (de)
AU (1) AU757318B2 (de)
BR (1) BR9910288A (de)
CA (1) CA2332039C (de)
DE (1) DE69905355T2 (de)
DK (1) DK1075284T3 (de)
ES (1) ES2192848T3 (de)
PL (1) PL194744B1 (de)
PT (1) PT1075284E (de)
SI (1) SI1075284T1 (de)
TR (1) TR200003279T2 (de)
WO (1) WO1999058159A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012135432A2 (en) 2011-03-29 2012-10-04 Kemin Industries, Inc. Dyes for membranes and biological structures

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0963759A1 (de) 1998-05-08 1999-12-15 Gerrit Reinold Jacob Melles Verwendung von einem Farbstoff zum Erleichtern der Entfernung einer Augenlinsentrübung
EP1132065A1 (de) * 2000-03-07 2001-09-12 Gerrit Reinold Jacob Melles Farbige visko-elastische Zusammensetzung
US6692526B1 (en) 2000-03-15 2004-02-17 Michael E. Snyder Ophthalmological surgery colorant and delivery system
DE10255601C5 (de) † 2002-10-14 2017-10-19 Fluoron Gmbh Verwendung eines Triphenylmethanfarbstoffs zur Herstellung eines Färbemittels bei der Netzhaut- und Glaskörperchirurgie
NL1025647C2 (nl) * 2004-03-05 2005-09-07 Dutch Ophthalmic Res Ct B V Inrichting voor het aanbrengen van vloeistof in het oog.
KR100950246B1 (ko) * 2005-05-20 2010-04-09 재단법인서울대학교산학협력재단 야누스 그린 ｂ를 포함하는 가시화 제제 및 이를 이용한가시화 방법
EP2140871A4 (de) 2007-04-06 2011-02-16 Senju Pharma Co Suspension zur visualisierung von transparenten augengeweben
DE102008064065B9 (de) 2008-12-19 2011-01-05 Fluoron Gmbh Farbstofflösung
US20110243850A1 (en) * 2008-12-25 2011-10-06 Canon Kabushiki Kaisha Probe for a biological specimen and labelling method and screening method using the probe
WO2010074325A1 (en) 2008-12-25 2010-07-01 Canon Kabushiki Kaisha Labeling composition for intraocular tissue, labeling method of intraocular tissue, and screening method
AU2011233815B2 (en) 2010-04-01 2015-03-19 D.O.R.C. Dutch Ophthalmic Research Center (International) BV Staining composition
EP2392355A1 (de) 2010-06-03 2011-12-07 Medical Technology Transfer Holding B.V. Farbzusammensetzung
EP2371395A1 (de) 2010-04-01 2011-10-05 Medical Technology Transfer Holding B.V. Farbzusammensetzung
FR2980363B1 (fr) * 2011-09-22 2014-11-28 Arcadophta Composition a toxicite reduite d'au moins un colorant stable et pouvant etre sterilisee
EP2620144A1 (de) 2012-01-27 2013-07-31 Medical Technology Transfer Holding B.V. Färbungszusammensetzung
US10493171B2 (en) * 2015-01-10 2019-12-03 Tamer Ahmet Seckin Laparoscopic surgery solution and method of using the same
JP2021522309A (ja) 2018-05-04 2021-08-30 フェネロン ホランド ホールディング ビー．ブイ． ヒアルロナンを可視化する為の可視化剤
EP4031069A1 (de) 2019-09-20 2022-07-27 Niios-USA Inc. Spender-overlay zur behandlung oder linderung von anterioren hornhautstörungen

Family Cites Families (4)

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Publication number Priority date Publication date Assignee Title
US4350676A (en) * 1981-05-21 1982-09-21 Laties Alan M Ophthalmic use of carboxyfluorescein
US4666699A (en) * 1985-03-04 1987-05-19 Allegheny-Singer Research Institute Stain-fixative composition for enteric parasites
US6024719A (en) * 1998-07-06 2000-02-15 Morris; Robert E Method and apparatus for performing surgery inside the human retina using fluidic internal limiting membrane (ILM) seperation (FILMS)
AUPQ155799A0 (en) * 1999-07-09 1999-08-05 Coroneo, Minas Theodore Therapeutic methods and uses

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012135432A2 (en) 2011-03-29 2012-10-04 Kemin Industries, Inc. Dyes for membranes and biological structures

Also Published As

Publication number Publication date
PT1075284E (pt) 2003-06-30
EP1075284A1 (de) 2001-02-14
CA2332039C (en) 2008-12-23
PL343925A1 (en) 2001-09-10
CA2332039A1 (en) 1999-11-18
JP2002514470A (ja) 2002-05-21
SI1075284T1 (en) 2003-08-31
AU757318B2 (en) 2003-02-13
WO1999058159A1 (en) 1999-11-18
JP3469198B2 (ja) 2003-11-25
DK1075284T3 (da) 2003-06-10
ES2192848T3 (es) 2003-10-16
ATE232400T1 (de) 2003-02-15
KR100711269B1 (ko) 2007-04-25
DE69905355T2 (de) 2004-02-12
PL194744B1 (pl) 2007-06-29
BR9910288A (pt) 2001-01-09
TR200003279T2 (tr) 2001-03-21
AU3853699A (en) 1999-11-29
EP0974367A1 (de) 2000-01-26
KR20010024991A (ko) 2001-03-26
US6696430B1 (en) 2004-02-24
DE69905355D1 (de) 2003-03-20

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